It is known that many antimicrobial drugs are becoming less effective against increasingly virulent and drug-resistant organisms. Hence, the benefits of new, more effective antimicrobial agents are well recognized.
Triclosan, (2,4,4′-trichloro-2′-hydroxydiphenyl ether), has been widely used for more than thirty years as an antibacterial agent in numerous consumer products, including toothpastes, mouthwashes, soaps, children's toys, and kitchen equipment. The widespread use of triclosan was predicated on the belief that triclosan acts through a non-specific mechanism involving bacterial membrane disruption. Triclosan was, therefore, assumed not to induce resistant strains of bacteria.
Recent findings, however, show that triclosan does not act non-specifically as originally thought, but rather, specifically, by inhibiting the fatty acid biosynthesis (FAS) pathway in certain bacteria and other organisms. In particular, it has been found that in numerous organisms, including Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and the malarial parasite Plasmodium falciparum, triclosan targets an NADH-dependent trans-2-enoyl-ACP reductase known as FabI. The foregoing organisms are believed to overcome the action of triclosan by mutating the gene that encodes FabI, also known as the fabI gene. Not surprisingly, then, it has also been found that triclosan is not immune to resistance, and that, in fact, bacteria are becoming increasingly triclosan-resistant.
A notable example of anti-bacterial resistance is found in the case of tuberculosis. Tuberculosis is a debilitating disease responsible for the deaths of three million people per year. Isoniazid, also known as isonicotinic acid hydrazide, or INH, is currently the most relied upon drug for the treatment of tuberculosis. Due to the increasing prevalence of resistance in Mycobacterium tuberculosis, current tuberculosis treatment regimens typically include the use of multiple antibiotics over an extended period of time. A typical regimen for treating tuberculosis is the administration of isoniazid, rifampicin, and pyrazinamide in combination with ethanbutol or streptomycin for two months, followed by the administration of isoniazid and rifampicin for four months.
Such multiple drug treatments, even if effective, have significant disadvantages, such as increased risk of side-effects by patients, prolonged treatment time, and high expense. In addition, multiple drug treatment is being severely compromised by the emergence of multi-drug resistant M. tuberculosis (MDR-TB).
As with triclosan, isoniazid targets the fatty acid synthase pathway of M. tuberculosis. In order to be effective, isoniazid requires activation by the mycobacterial catalase-peroxidase enzyme KatG.
At least one mode by which M. tuberculosis resists isoniazid is a genetic mutation of the KatG enzyme. The alteration of the KatG enzyme disables the activation of isoniazid, thereby significantly reducing the efficacy of the drug.
The diazaborines are another class of compounds known to target FabI in E. Coli. The diazaborines form a covalent adduct with the NAD(H) cofactor. Diazaborine-resistant organisms arise from genetic mutations that alter the residues that form the NAD-diazaborine binding pocket, thereby reducing the affinity of the drug for the enzyme.
Accordingly, there is a need for new and improved antimicrobial compounds that are effective against increasingly virulent and drug-resistant organisms, and that overcome the limitations of the drugs described thus far.